Project Summary/Abstract This proposal investigates how the coordinated evolution of transposable elements (TEs) and KRAB zinc finger proteins (KZNFs) have uniquely shaped human embryonic development at the molecular level. KRAB Zinc Fingers are the largest family of human transcription factors and have undergone rapid evolution in order to regulate TE expression. Furthermore, aberrant TE and KZNF expression is associated with a multitude of human disease phenotypes, including developmental defects and many cancers and neurological diseases. In this proposal, I hypothesize that that the evolutionary interplay between KZNFs and TEs has led to key changes in gene expression patterns, and that these changes have led to changes in human embryonic development that differentiate humans from other primates. I propose two major aims to test this hypothesis: 1) Determine the features of KZNF-TE recognition for established KZNF-TE pairs by using bioinformatics-based approaches and reporter assays. 2) Perturb KZNF-TE interactions in primate stem cell models to establish their role in species-specific embryonic development pathways. The results of this work will increase understanding of how TEs and KZNFs have influenced human development, providing a solid foundation for developing treatments for many TE-associated disease states.